The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant pathogens. Such bacteria are associated with significant morbidity and mortality. A number of possible solutions to the developing bacterial resistance problem have been suggested (Silver, L. L.; Bostian, K. A. Antimicrob. Agents Chemother. 1993, 37, 377). Overall, the best overall solution to the bacterial resistance dilemma continues to be the identification and development of structurally novel antibacterial agents employing a unique mechanism of action (Chopra, I. et al. JAMA, 1996, 275, 401).
For instance, the quinolones are a widely prescribed group of bacterial DNA gyrase inhibitors. DNA gyrase is a tetrameric enzyme composed of two GyrA and two GyrB subunits that negatively supercoils DNA by a sequence of strand breaking, passage of the DNA through the interior of the enzyme complex, and resealing. The quinolines act at the GyrA subunit. Their mechanism of action involves stabilization or trapping of the cleaved gyrase-DNA complex. This inhibits the function of the essential DNA gyrase and leads to cell death. It should also be noted that the quinolones also inhibit, to varying degrees, bacterial topoisomerase IV, an essential tetrameric enzyme involved in the initiation of DNA decatenation, the process by which two daughter chromosomes are separated after division of a bacterial chromosome. Topoisomerase IV is composed of two ParC and two ParE subunits, which exhibit structural similarity to GyrA and GyrB, respectively. Representative quinolones include the fluoroquinolones ciprofloxacin, levofloxacin and gatifloxacin. Bacterial resistance to the fluoroquinolones is becoming increasingly problematic (Kotilainen, P. et al. J. Infect. Dis. 1990, 161, 41–44. Trucksis, M. et al. Ann. Intern. Med. 1991, 114, 424–426. Chen, D. K. et al. N. Engl. J. Med. 1999, 34, 233–239).
Bacterial DNA gyrase inhibitors that complement the activity of the quinolones by inhibiting the GyrB subunit have also been identified. The coumarins, exemplified by novobiocin and coumermycin A1, and the cyclothialidines are representative GyrB inhibitors that bind to the ATP recognition site of the subunit. Unfortunately, novobiocin has limited therapeutic value due to the observation of rapid resistance development during treatment and other limitations (Kim, O. K. et al. Exp. Opin. Ther. Patents 1998, 8, 959–969. Maxwell, A. Trends in Microbiology, 1997, 5, 102–109. Maxwell, A. Mol. Microbiol. 1993, 9, 681–686). The cyclothialidines suffer from drug metabolism issues (Boehm, H.-J. et al. J. Med. Chem. 2000, 43, 2664–2674).